Patients having von Willebrand's disease (vWD), blood coagulation disorders, such as hemophilia A, and including various hemostatic disorders such as uremia, cirrhosis, congenital platelet defects, congenital and acquired storage pool deficiency, and patients with unexplained prolongations of bleeding time, are exposed to risks of viral infection when treated with plasma derivatives. Even patients with mild forms of these disorders who normally require no supplementation with blood products are exposed to these risks when surgical procedures are undertaken.
Von Willebrand factor (vWF) is a heterogeneous, multimeric plasma glycoprotein (Zimmerman T S, Roberts J, Edgington T S: Factor VIII-related antigen: multiple molecular forms in human plasma. Proc Natl Acad Sci USA 72:5121, 1975; Hoyer L W, Shainoff J R: Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers. Blood 55:1056, 1980) that plays an important role in platelet adhesion (Sakariassen K S, Bolhuis P A, Sixma J J: Human blood platelet adhesion to artery subendothelium is mediated by factor VIII/von Willebrand factor bound to the subendothelium. Nature 279:636, 1979; Stel H V, Sakariassen K S, de Groot P G, et al: von Willebrand factor in the vessel wall mediates platelet adherence. Blood 65:85, 1985; Turitto V T, Weiss H J, Zimmerman T S, et al: Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion. Blood 65:623, 1985) and also functions as the plasma binding (carrier) protein for factor VIII.
Deficiency of vWF has two consequences: platelet dysfunction and decreased concentration of factor VIII. In von Willebrand's disease (vWD), a common inherited bleeding disorder in which either the concentration or multimer pattern of vWF is abnormal, mucocutaneous bleeding related to platelet dysfunction is the predominant clinical feature. In the most common form of vWD (Type I), patients have a mild to moderate decrease in plasma vWF with a normal multimer pattern. Other forms of vWD are characterized by severe deficiencies of vWF or by abnormal multimer patterns which can be distinguished from the normal pattern electrophoretically.
Mannucci, Blood, 72(5):1449-1455 (1988), describes a non-transfusional form of treatment for congenital and acquired bleeding disorders in which desmopressin (1-desamino-8-D-arginine vasopressin; DDAVP), a synthetic analogue of the anti-diuretic hormone L-arginine vasopressin, transiently raises the circulating levels of factor VIII coagulant activity and von Willebrand factor and thereby shortens the prolonged bleeding time in patients with Type I vWD. DDAVP has been established as a non-transfusional form of treatment for mild and moderate hemophilia and von Willebrand Disease. The first clinical applications of these findings were published in 1977. Mannucci et al., The Lancet Ltd, pp. 869-872 (Apr. 23, 1977). Other treatments, such as the use of compounds such as adrenaline, vasopressin, and insulin can all induce short-term increases in endogenous factor VIII and von Willebrand factor in healthy volunteers as well as in patients with hemophilia A and vWD. Not only has DDAVP been shown to be effective in the treatment of minor bleeding episodes in patients with mild deficiency of factor VIII (hemophilia A), but also, DDAVP has shown the ability to improve bleeding times in patients with platelet dysfunction due to uremia. In all of these conditions, DDAVP is thought to transiently increase plasma vWF concentrations by stimulating the release of stored pools of vWF from vascular endothelial cells. The clinical use of DDAVP is limited by the short duration of its effect on vWF (approximately 12 hours) and a phenomenon known as tachyphylaxis (decreased response with repeat dosing).
Of general background interest to the present invention is Greenberg et al., Exp. Hematol., 19:53-58 (1991), who describe an assay of megakaryocyte maturation utilizing vWF synthesis as a marker of development. IL-6 gave increased vWF production.
Holzinger et al., Immunology Letters, 35:109-118 (1993), studied human umbilical vascular endothelial cells (HUVEC). It was found that the vWF content of these cells was reduced upon administration of IFN-.gamma., or IL-1. Endothelial cells are able to produce vWF. With these isolated cells, while IL-1 and IFN-.gamma. inhibited vWF production, the other cytokines used in the study (IL-2, IL-6, GM-CSF) were not effective.
An in vivo study, Burstein et al., Thrombosis and Haemostasis, 69:749 (1993), disclose that the administration of interleukin-6 (IL-6) to dogs augments the platelet count, platelet size and plasma fibrinogen levels in normal and thrombocytopenic animals. They also observed an increase in vWF levels ranging from 2.7 to 3.6 times baseline levels between two and nine days and normalization thereafter.
Montgomery, Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Ch. 7; 3rd Ed., J. B. Lippincott Co., Philadelphia, Pa. (1994) provide a summary of vWD as well as forms of treatment.
There continues to be a need in the art for alternative products in the treatment of bleeding disorders and the like.